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Huntington Disease (HD) is a dominantly inherited neurological disease attributed to a CAG expansion within the HD gene. The HD mutation gives rise to a polyglutamine expansion in exon 1 of the protein huntingtin (Htt). Since the discovery of the HD mutation in 1993, various HD gene mouse models have been developed to contain either fragments or full-length copies of the mutant HD gene. The existence of these HD mouse models enables focused therapeutic testing to develop potential treatments for HD. RNA interference (RNAi) therapy is a targeted gene silencing approach whereby synthetic RNA constructs are shuttled into the cell by viral vectors and used by the cell’s endogenous RNAi machinery to silence a gene of interest. RNAi therapy holds promise for mutant huntingtin (muHtt) allele-specific silencing as a treatment for HD. The purpose of this thesis was to develop the tools for pre-clinical testing of RNAi-mediated gene silencing of human muHtt in the YAC128 mouse model of HD. First, AAV serotypes were compared for delivery to striatal neurons, the neurons most affected in HD. From this work AAV serotype 1 was selected as the most effective serotype for construct delivery. Second, synthetic RNAi constructs including short-hairpin RNA (shRNA) and microRNA-based constructs (miR-shRNAs) were compared for silencing of human muHtt expression in vivo. Here, miR-shRNAs were found to have increased gene silencing and improved tolerance in avoiding immune activation compared to shRNAs. Alternatively, the shRNAs induced dramatic immune activation and morbidity in some cases. Ultimately these findings will contribute to a pre-clinical trial in YAC128 mice investigating Htt RNAi-mediated gene silencing in the treatment of HD, which is also discussed in this thesis. This future work provides proof-of-principle for muHtt allele-specific silencing as a treatment of HD.